Research

The Stanfield Lab investigates how oncogenic viruses initiate infection, evade host defenses, and drive cancer development. Our central mission is to create and refine immune-competent guinea pig models that bridge the gap between basic virology and translational medicine. By combining primary cell culture, in vivo pathogenesis studies, and advanced genomics, we aim to uncover how viruses such as Kaposi's sarcoma–associated herpesvirus (KSHV), Epstein–Barr virus (EBV), and Human papillomavirus (HPV) establish infection and promote tumorigenesis.

Guinea pigs provide a uniquely valuable system: their immune and physiological responses often parallel those of humans more closely than traditional murine models. We leverage this platform to model virus–host interactions, test therapeutic strategies, and expand the toolkit for studying host-restricted pathogens that have lacked tractable small-animal models. Our work spans from herpesvirus-associated lymphomas and sarcomas to HPV-driven cervical cancers, providing comprehensive models for viral oncology research.

Research Impact

Our guinea pig models are advancing viral oncology across herpesvirus and papillomavirus-associated cancers, providing new tools for preclinical drug and vaccine development.

Current focus areas

Innate Immune Signaling: Guinea Pig vs Human Responses to KSHV

Guinea Pig — Activated Human — KSHV Suppression dsRNA (viral) MDA5 MAVS IRF7 Type I IFN KSHV miRNAs Seed mismatch → Weak inhibition vIRF-3 (K10.5) Poor GP IRF7 binding → Reduced inhibition MDA5 MAVS IRF7 Type I IFN ↓ KSHV miRNAs Target IFIH1 (MDA5) → Strong repression vIRF-3 (K10.5) Binds and blocks IRF7 → Effective inhibition Summary: Guinea pig cells maintain stronger innate immunity against KSHV due to sequence mismatches that reduce viral miRNA efficacy and altered protein-protein interactions that weaken vIRF-3 inhibition of IRF7. This results in preserved MDA5→MAVS→IRF7→Type I IFN signaling compared to strong suppression in human cells.
Guinea pig cells show enhanced MDA5→MAVS→IRF7 activation due to reduced KSHV miRNA and vIRF-3 inhibition compared to human cells.

KSHV Endothelial Cell Transformation and Kaposi's Sarcoma Development

Entry & Attachment Heparan sulfate Integrins (αVβ3, α3β1) EphA2, DC-SIGN Acute Signaling FAK/Src → PI3K-AKT MAPK/ERK activation NF-κB survival signals Latency Programs LANA vCyclin vFLIP K1 Paracrine Factors vIL-6 vGPCR VEGF KS-like Lesion Spindle cell morphology Vascular architecture Inflammatory infiltrate Oncogenic Hallmarks • Enhanced angiogenesis (VEGF/HIF-1α) • Deregulated proliferation (vCyclin-CDK6) • Survival signaling (vFLIP → NF-κB) • Immune evasion (viral miRNAs) Transformation pathway: KSHV entry via multiple receptors activates survival pathways (PI3K-AKT, NF-κB). Latency genes LANA, vCyclin, vFLIP, and K1 drive transformation while paracrine factors (vIL-6, vGPCR, VEGF) promote angiogenesis and immune evasion, resulting in characteristic KS-like vascular lesions.
KSHV endothelial transformation progresses through receptor engagement, acute signaling, latency establishment, and paracrine-driven angiogenesis.

HPV Cervical Cancer Progression and Therapeutic Vaccine Strategy

Normal Cervical Epithelium Stratified squamous Normal differentiation HPV 16/18 E6/E7 E6 → p53 ↓ E7 → pRb ↓ CIN 1 Low-grade Mild dysplasia Often reversible CIN 2/3 High-grade Severe dysplasia Precancerous Invasive Cervical Carcinoma Invasive disease Mouse Models TC-1, C3-Tag Guinea Pig Models Enhanced human similarity E6/E7 Therapeutic Vaccine • Target existing lesions • CD8+ T cell responses • Tumor regression • Prevention of recurrence Immune Activation CTL clearance Memory formation Therapeutic strategy: HPV E6/E7 oncoproteins drive progression from normal cervix through CIN to invasive carcinoma. E6/E7-targeted therapeutic vaccines tested in mouse models (TC-1, C3-Tag) and novel guinea pig models activate CD8+ T cells to clear existing lesions and prevent progression to invasive disease.
HPV E6/E7-driven cervical cancer progression with therapeutic vaccine intervention targeting existing lesions and preventing recurrence.

L2C Guinea Pig Lymphoma Model for Therapeutic Development

Normal B Cell L2C Lymphoma Malignant B cells BCR → BTK → NF-κB Survival addiction pathway Syngeneic GP Model • Strain 2 guinea pigs • Immune competent • Tumor growth kinetics Single-cell Analysis • scRNA-seq profiling • Genomic characterization • Drug response signatures Mantle Cell Lymphoma Chronic Lymphocytic Leukemia BTK Inhibitor Testing Ibrutinib Acalabrutinib Zanubrutinib Next-generation Outcomes • Efficacy • Toxicity • Resistance Transformation Inoculation Profile Models L2C model advantages: Syngeneic guinea pig B-cell lymphoma with BCR→BTK→NF-κB addiction enables comprehensive BTK inhibitor pharmacology. Single-cell genomics positions L2C as analog for human MCL and CLL, providing immune-competent platform for preclinical therapeutic evaluation.
L2C model with BCR→BTK→NF-κB signaling addiction enables BTK inhibitor testing with single-cell profiling and human disease correlation.

Comparative Virology and Host Adaptation Engineering

Human-Restricted Viruses KSHV (HHV-8) EBV (HHV-4) Related Animal Viruses RRV Rhesus GPHLV GP herpes-like GPXV GP X virus Adaptation Engineering Host Tropism Receptor binding Entry mechanisms Immune Evasion Species-specific vIRFs miRNA seed matches Engineering Strategy Modify receptor binding domains, immune evasion genes Optimize for guinea pig host factors Guinea Pig-Adapted KSHV-GP Engineered strain EBV-GP Engineered strain Guinea Pig Host System • Immune competent • Enhanced human similarity • Pathogenesis studies • Therapeutic testing In Vivo Validation • Infection kinetics and tropism • Pathogenesis patterns • Immune responses and clearance Analysis Engineer Insights Validate Comparative approach: Study related herpesviruses (RRV, GPHLV, GPXV) to understand host adaptation mechanisms. Engineer guinea pig-adapted KSHV and EBV strains by modifying receptor binding and immune evasion genes. Validate tropism, pathogenesis, and therapeutic responses in vivo.
Using related herpesviruses (RRV, GPHLV, GPXV) to guide engineering of guinea pig-adapted strains with validation of tropism and pathogenesis.

Comprehensive Preclinical Testing Platform

Guinea Pig Cancer Models KSHV • EBV • HPV L2C lymphoma Antivirals • Nucleoside analogs • Protease inhibitors • Entry inhibitors Therapeutic Vaccines • E6/E7 targeting • Viral antigens Epigenetic Modulators • HDAC inhibitors • G4 stabilizers Targeted Therapies • BTK inhibitors • Kinase inhibitors Immunotherapies • Checkpoint inhibitors • Adoptive cell therapy • mAbs Combination Therapies • Multi-target • Synergistic effects Outcomes • Viral load • Tumor burden • Survival • Immune activation Platform integration: Comprehensive therapeutic evaluation across multiple modalities using guinea pig viral cancer models with standardized outcomes.
Integrated platform testing antivirals, vaccines, epigenetic modulators, targeted and immune therapies with standardized outcome measures.

Single-cell Genomics and Systems Biology Approaches

Tumor Tissue Mixed populations: Tumor • Immune • Stroma Cell Dissociation Single cell suspension 10X Genomics scRNA-seq Cell barcoding + UMI Data Analysis QC Filter Normalize Cluster UMAP Cell Type ID Cell Populations Tumor cells CD8+ T cells CD4+ T cells B cells Macrophages Pathway Analysis • GSEA enrichment • Viral gene programs • Host immune responses • Cell-cell communication Spatial Validation • Immunohistochemistry • In situ hybridization • Tissue architecture • Biomarker validation Systems Integration • Multi-omics analysis • Network modeling • Drug synergy prediction • Biomarker discovery Model Applications KSHV HPV L2C Therapeutic responses Integrated workflow: From tissue dissociation to single-cell sequencing, clustering, and pathway analysis. Results validated through spatial methods (IHC, ISH) and integrated with systems approaches for biomarker discovery across KSHV, HPV, and lymphoma models.
Comprehensive single-cell workflow from tissue to pathway analysis with spatial validation and systems integration across disease models.

Together, these efforts define a comprehensive program in viral oncology: connecting molecular mechanisms of viral pathogenesis to clinically relevant animal models across herpesvirus and papillomavirus systems. By expanding the guinea pig as a small-animal model for KSHV/EBV-associated cancers and HPV cervical cancer, we aim to deliver practical tools for understanding—and ultimately intervening in—the full spectrum of virus-associated cancers.